BLU-5937, BELLUS Health's lead drug candidate, is a potent, highly selective, orally bioavailable small molecule antagonist of the P2X3 receptor, a clinically validated target for chronic cough. BLU-5937 has the potential to be a best-in-class therapeutic for chronic cough patients who do not respond to current therapies.

On November 19, 2018, BELLUS Health announced the positive top-line results from the clinical Phase 1 study for BLU-5937. The Phase 1 top-line data demonstrated that BLU-5937 has a good safety and tolerability profile, as well as a pharmacokinetic profile supporting twice-a-day (BID) dosing. At the anticipated therapeutic doses of 50 to 100 mg, BLU-5937 did not cause any loss of taste perception.

Based on these positive Phase 1 data, the Company intends to advance BLU-5937 into a clinical Phase 2 study in chronic cough patients beginning in mid-2019, with top-line results anticipated in mid-2020. This will be a dose escalation crossover design study to assess the safety, tolerability and efficacy of BLU-5937 in chronic cough patients, in addition to helping confirm the optimal dose regimen.

Clinical Phase 1 Study Data

On November 19, 2018, BELLUS Health announced the positive top-line results from the clinical Phase 1 study for BLU-5937.

The Phase 1 data demonstrated that BLU-5937 has an excellent pharmacokinetic profile. Plasma half-life was established at approximately 5 hours, supporting BID dosing. Based on pre-clinical efficacy studies and comparison with drug levels achieved with a clinically validated comparator, the Company anticipates that drug levels required for optimal inhibition of cough will be achieved at 50 mg or 100 mg BID.

BLU-5937 plasma concentration increased dose-proportionally and was not affected by food, supporting BLU-5937 administration without regard to meals.

The Phase 1 data also showed that BLU-5937 has a good safety and tolerability profile. The overall incidence of adverse events was comparable between placebo (56%) and BLU-5937 (47%).

There were no serious adverse events and no subjects withdrew prematurely due to an adverse event during the study. No significant trends of mean changes in vital signs, electrocardiogram (ECG) and clinical laboratory values have been observed in the Phase 1 study for BLU-5937.

No subject reported total loss of taste at any dose level. Only one subject out of 24 (4.2%) reported taste alteration at the anticipated therapeutic doses of 50-100 mg. This taste effect was reported only on the first day out of 7 days of dosing in a subject receiving 100 mg BID. At supra-therapeutic doses of 200 mg to 1200 mg, two subjects out of 48 (4.2%) reported mild, transient partial loss of taste and 13 subjects out of 48 (27.1%) reported taste alteration. No subject out of 16 reported any taste loss or taste alteration at 200 mg. All taste adverse events were transitory and sporadic in nature and almost all of them were mild. The other most frequent adverse events reported in the Phase 1 study (> 5%) for BLU-5937 were: headache (12.5%), numbness (11.1%), nausea (8.3%), dizziness (8.3%) and heartburn (5.6%).

Clinical Phase 1 Study

The clinical Phase 1 study was a randomized, double-blind, placebo-controlled study of orally administered BLU-5937 in 90 healthy adult subjects. The primary objectives of the clinical Phase 1 study were to assess the safety, tolerability (including taste perception) and pharmacokinetic profile of BLU-5937 in healthy subjects.

The study was divided in two parts:

Part 1: A single ascending doses (SAD) study was conducted in 60 healthy subjects. Subjects were randomized into 6 cohorts of 10 subjects (8 BLU-5937: 2 placebo). The study evaluated single oral doses of BLU-5937 from 50 to 1200 mg.

Clinical Phase 2 Study Design

Based on the positive top-line data from the Phase 1 study, BELLUS Health expects to initiate a clinical Phase 2 study for BLU-5937 in chronic cough patients in mid-2019, with top-line results anticipated in mid-2020. This will be a dose escalation crossover design study to assess the safety, tolerability and efficacy of BLU-5937 in chronic cough patients, in addition to helping confirm the optimal dose regimen. A total of 50 patients with refractory unexplained chronic cough are expected to be enrolled in approximately 10 clinical sites located in the United Kingdom and Unites States.

In September 2018, the Company announced the appointment of an international clinical advisory board (the “CAB”), which will provide strategic guidance and support to the BLU-5937 development program as the Company prepares for the clinical Phase 2 study. The CAB is comprised of highly-respected clinical leaders whose work has influenced the treatment and management of chronic cough. The Chair of the CAB is Dr. Jaclyn Smith, MB, ChB, FRCP, PhD, Professor of Respiratory Medicine at the University of Manchester in the United Kingdom and an Honorary Consultant at the University Hospital of South Manchester NHS Foundation Trust.

The preclinical toxicology studies also demonstrated an excellent safety profile for BLU-5937.

BLU-5937’s Reduction in Cough Frequency Comparable to the Leading P2X3 Antagonist, Gefapixant

The anti-tussive effect of BLU-5937 was compared to that of gefapixant in a guinea pig cough model. Treatments (control, BLU-5937 (0.3, 3 and 30 mg/kg) or gefapixant (0.3, 3 or 30 mg/kg)) were administered orally in seven groups of 6 animals 2 hours prior to tussive agent exposure (citric acid and histamine) and the number of coughs were counted for a period of 15 minutes. Both treatments showed comparable dose-dependent reduction in cough frequency as compared to the control. The reduction in cough was statistically significant at 3 mg/kg (39% vs. control) and 30 mg/kg (52% vs. control) with BLU-5937, and at 30 mg/kg (45% vs. control) with gefapixant.

BLU-5937’s Duration of Effect also Comparable to Gefapixant

Using the same guinea pig cough model, a time course study was conducted to assess the duration of the anti-tussive effect of BLU-5937 and gefapixant following the administration of a single oral 30mg/kg dose. In this study, animals in groups of 6 were exposed to tussive agents (citric acid and histamine) at various times after the administration of the study drugs (2, 4, 6, 8 and 12 hours post-dose for BLU-5937 and 2 and 8 hours post-dose for gefapixant) and the number of coughs were measured for 15 minutes. The reduction in cough frequency compared to control was shown to be statistically significant at 2, 4 and 6 hours post-dose with BLU-5937, and at 2 hours post-dose with gefapixant. The anti-tussive effect was no longer significant at 8 hours post-dose for both agents. These results indicate that BLU-5937 and gefapexiant have comparable duration of effect.

A rat taste model was used to compare BLU-5937’s effect on taste function with that of gefapixant. Animals were water-fasted overnight and presented with one bottle of water and one bottle of (bitter-tasting) quinine at the time corresponding to the maximum plasma concentration of study drugs; and the volume of liquid consumed from each bottle was measured for 15 minutes. Treatments (control, BLU-5937 (10 or 20 mg/kg) or gefapixant (10 or 20 mg/kg)) were administered intraperitoneally in two groups of 10 rats. Animals treated with BLU-5937 did not drink more quinine than the control animals, while those treated with gefapixant drank significantly (approximately 5 times) more quinine than the control at the two doses tested. These results indicate that gefapixant led to significant taste loss, while BLU-5937 was not associated with taste loss.

Disease and Market

Chronic cough is associated with significant adverse social, psychosocial and physical effects on quality of life. Chronic cough, defined as a cough that lasts more than eight weeks, is estimated to affect approximately 10% of adults in the U.S. While an underlying etiology may contribute to cough in some of these patients, including gastro-oesophageal reflux, asthma, or allergic rhinitis, an underlying condition cannot be identified in 10%-20% of chronic cough patients (unexplained chronic cough). A portion of patients with an underlying condition as well as the large majority of unexplained chronic cough patients are not well controlled by current therapies.

In June 2017, the Company commissioned Torreya Insights LLC to conduct a market assessment through an evaluation of chronic cough epidemiology and pricing estimates. Based on primary and secondary research, the report concludes that, in the United States alone, more than 26 million adults suffer from chronic cough and more than 2.6 million of these patients have chronic cough lasting for more than a year. The number of treatment-refractory chronic cough patients expands to 11.7 million when taking into account those patients with a cough duration between eight weeks and one year. The market assessment also sought to better understand the pricing and reimbursement landscape for a condition that has no recently-approved therapies, and therefore no direct comparables. Based on interviews with Key Opinion Leaders, prescribing physicians and payers, the consensus is that new chronic cough treatments, such as BLU-5937, will be priced similarly to therapies for chronic constipation, asthma and partial onset seizures. These analogs represent non-lethal chronic conditions that have a significant impact on quality of life and address a large patient population in competitive markets that also include generic and over-the-counter products. The monthly price for these analogs varies between US $300 and $600.

In October 2018, BELLUS Health announced that the U.S. Patent and Trademark Office had issued U.S Patent No. 10,111,883, granting claims for the use of BELLUS Health's lead drug candidate BLU-5937 for the treatment of chronic cough without affecting taste response. More generally, the patent entitled “Selective P2X3 Modulators” claims the use of imidazopyridine compounds that are selective for the P2X3 receptor as a means of minimizing taste perturbation in patients treated for chronic cough. In addition to BLU-5937, the patent claims the use of related selective imidazopyridine compounds and pharmaceutical compositions comprising BLU-5937. Patent No. 10,111,883 has an expiration date of 2038, excluding any potential patent term extension. This new U.S. patent extends the patent protection of BLU-5937 by an additional 4 years.

In July 2018, the Company announced that patent protection for BLU-5937 had been secured in all major pharmaceutical markets following the Japan Patent Office’s issuance of a decision to grant a patent for claims covering the composition of matter of BLU-5937 and related imidazopyridine compounds, in addition to pharmaceutical compositions comprising BLU-5937 and uses thereof, until 2034. Equivalent patents with similar broad claims were granted by the European Patent Office in April 2018 and by the U.S. Patent and Trademark Office and the Chinese Patent Office in 2017. The patents have an expiration date of 2034, excluding any potential patent term extension. Patent applications with similarly broad claims are currently pending in other industrialized nations.